Nickel allergy and hand eczema – epidemiological aspects To my family Örebro Studies in Medicine 47 Anna Josefson Nickel allergy and hand eczema – epidemiological aspects © Anna Josefson, 2010 Title: Nickel allergy and hand eczema – epidemiological aspects. Publisher: Örebro University 2010 www.publications.oru.se [email protected] Printer: Intellecta Infolog, Kållered 11/2010 issn 1652-4063 isbn 978-91-7668-765-9 ABSTRACT Anna Josefson (2010) Nickel allergy and hand eczema --- epidemiological aspects. Örebro studies in medicine 47, 73 pp. Nickel allergy is the most prevalent contact allergy and has been discussed as a possible risk factor for hand eczema. However, hand eczema is one of the most frequently occurring skin diseases and has multifactorial origin. The aim of this thesis was to study the association between nickel allergy and hand eczema in the general population. There are only a few population-based studies previously published, that include patch testing. In addition, this thesis aimed to evaluate methods to follow the prevalence of nickel allergy. The study cohort consisted of 908 women who had been patch tested for the occurrence of nickel allergy as schoolgirls. Twenty years later, they were invited to participate in a follow-up questionnaire study. The response rate was 81%. In total, 17.6% of respondents reported hand eczema after the age of 15 years and there was no statistically significant difference in the occurrence of hand eczema between those who were nickel-positive and those who were nickel- negative as schoolgirls. To further investigate possible links, another study was performed, which included a second questionnaire, a clinical investigation and patch testing. All schoolgirls from the baseline study who were still living in the area as adults were invited to participate and the participation rate was 77%. Patch test showed 30.1% nickel-positive individuals. When all participants were included in the analysis, there was no statistically significant difference between nickel-positive and nickel-negative women regarding occurrence of hand eczema. The most important risk factor for hand eczema was childhood eczema. Adjusted prevalence proportion ratio (PPR) for hand eczema after age 15 in relation to nickel patch test results was 1.03 (95% CI 0.71---1.50) and in relation to childhood eczema 3.68 (95% CI 2.45--- 5.54). When women with and without history of childhood eczema were analyzed separately, the hand eczema risk was doubled in nickel-positive women without history of childhood eczema. In conclusion, the risk of hand eczema in nickel-positive women may previously have been overestimated. Next, the validity of self-reported nickel allergy was investigated. In the established cohort; two questions regarding nickel allergy were compared with patch test results. The validity of self-reported nickel allergy was low, and the questions regarding nickel allergy overestimated the true prevalence of nickel allergy. The positive predictive values were 59% and 60%. Another method for estimating the prevalence of nickel allergy, namely self-patch testing, was validated in the last study. In total, 191 patients from three different dermatology departments participated. The validity of self-testing for nickel allergy was adequate, with sensitivity 72% and proportion of agreement 86%. Keywords: childhood eczema, contact allergy, patch test, population-based, predictive value, questionnaire, self-test, sensitivity, specificity, validity, wet work Anna Josefson, Department of Dermatology, Örebro University Hospital, SE-701 85 Örebro, Sweden. E-mail: [email protected] SAMMANFATTNING PÅ SVENSKA Nickelallergi är vanligt förekommande. Prevalensen i Skandinavien är 15---25% hos kvinnor och cirka 3% hos män. Sambandet mellan nickelallergi och uppkomst av handeksem har tidigare diskuterats och i vissa studier anges att 30---45% av alla individer med nickelallergi får handeksem. Det finns dock endast ett fåtal publicerade studier där personer ur normalbefolkningen har lapptestats för nickel. Handeksem är vanligt och har ofta flera olika kombinerade orsaker. Det övergripande syftet med avhandlingen var att studera nickelallergins betydelse för uppkomst av handeksem. Det finns ett intresse av att följa förekomsten av nickelallergi över tid, speciellt sedan det i början av 2000-talet infördes ett EU-direktiv som begränsar nickelinnehåll i klockor, smycken, metallknappar etc. Ytterligare ett syfte med avhandlingen var att utvärdera epidemiologiska metoder för att följa förekomsten av nickelallergi. Den första studien var en uppföljningsstudie av 908 flickor ur normalbefolkningen, vilka i skolåldern lapptestats med nickel. Tjugo år senare skickades en enkät till dessa kvinnor, svarsfrekvensen var hög (81%). Förekomsten av självrapporterat handeksem efter 15 års ålder var 17.6%. Det förelåg ingen signifikant skillnad i förekomst av handeksem mellan de kvinnor som var nickelallergiska som barn jämfört med dem som inte var nickelallergiska. År 2006 utfördes ytterligare en studie, som inkluderade de kvinnor som fortfarande bodde i Örebro län. Studien omfattade en klinisk undersökning av händerna samt ett lapptest. 30% av kvinnorna var positiva för nickel. Det förelåg ingen signifikant skillnad i förekomst av handeksem mellan de som var positiva för nickel och de som var negativa. Vid separat analys av de kvinnor som angav tidigare barneksem jämfört med dem som aldrig hade haft barneksem visade det sig att risken för handeksem var dubbelt så stor hos nickelallergiker i den gruppen som aldrig hade haft barneksem. Båda studierna visade att barneksem var den största riskfaktorn för att få handeksem som vuxen, med en 3-4 gånger ökad risk. Den tredje studien var en validering av självrapporterad nickelallergi. Överensstämmelsen var låg mellan enkätfrågor gällande nickelallergi och lapptestverifierad nickelallergi. Av dem som själva bedömde sig vara nickelallergiska var endast 59% positiva enligt lapptest. För att följa förekomsten av nickelallergi i befolkningen behövs därför andra metoder. I den fjärde studien utvärderades ett självtest för nickelallergi. 191 patienter från tre olika hudkliniker i Sverige deltog i studien. Validiteten för metoden självtest var tillfredsställande, sensitiviteten var 72% och graden av överensstämmelse var 86%. CONTENTS ABBREVIATIONS .............................................................................10 LIST OF PUBLICATIONS........................................................................11 INTRODUCTION .....................................................................................13 BACKGROUND .......................................................................................15 Contact allergy and patch testing ...........................................................15 Nickel allergy .........................................................................................19 Hand eczema ..........................................................................................21 Nickel allergy and hand eczema .............................................................24 Atopic dermatitis ....................................................................................27 Hand eczema, contact allergy and recent research on genetics ..............28 Epidemiological surveillance of contact allergy .....................................29 AIMS OF THE THESIS ...........................................................................33 SUBJECTS AND METHODS ...................................................................35 Part I: Hand eczema and nickel allergy (study I–II)...............................35 Part II: Methods for epidemiological surveillance of nickel allergy (study III–IV) ...................................................................39 Ethics ......................................................................................................41 RESULTS ................................................................................................43 Part I: Hand eczema and nickel allergy (study I–II)...............................43 Part II: Methods for epidemiological surveillance of nickel allergy (study III–IV) ...................................................................49 DISCUSSION ..........................................................................................53 Part I: Hand eczema and nickel allergy (study I–II)...............................53 Part II: Methods for epidemiological surveillance of nickel allergy (study III–IV) ...................................................................57 Final remarks ..........................................................................................60 CONCLUSIONS ......................................................................................61 ACKNOWLEDGEMENTS .........................................................................63 REFERENCES .................................................................................65 PAPERS I–IV ..........................................................................................75 CONTENTS ABBREVIATIONS .............................................................................10 LIST OF PUBLICATIONS........................................................................11 INTRODUCTION .....................................................................................13 BACKGROUND .......................................................................................15 Contact allergy and patch testing ...........................................................15 Nickel allergy .........................................................................................19 Hand eczema ..........................................................................................21 Nickel allergy and hand eczema .............................................................24 Atopic dermatitis ....................................................................................27 Hand eczema, contact allergy and recent research on genetics ..............28 Epidemiological surveillance of contact allergy .....................................29 AIMS OF THE THESIS ...........................................................................33 SUBJECTS AND METHODS ...................................................................35 Part I: Hand eczema and nickel allergy (study I–II)...............................35 Part II: Methods for epidemiological surveillance of nickel allergy (study III–IV) ...................................................................39 Ethics ......................................................................................................41 RESULTS ................................................................................................43 Part I: Hand eczema and nickel allergy (study I–II)...............................43 Part II: Methods for epidemiological surveillance of nickel allergy (study III–IV) ...................................................................49 DISCUSSION ..........................................................................................53 Part I: Hand eczema and nickel allergy (study I–II)...............................53 Part II: Methods for epidemiological surveillance of nickel allergy (study III–IV) ...................................................................57 Final remarks ..........................................................................................60 CONCLUSIONS ......................................................................................61 ACKNOWLEDGEMENTS .........................................................................63 REFERENCES .................................................................................65 PAPERS I–IV ..........................................................................................75 ABBREVIATIONS ACD Allergic contact dermatitis AD Atopic dermatitis CI Confidence interval D Day HECSI Hand Eczema Severity Index ICDRG International Contact Dermatitis Research Group IR Irritant reaction NPV Negative predictive value PPR Prevalence proportion ratio PPV Positive predictive value SPSS Statistical Package for the Social Sciences 10 10